Abstract SuddenCardiacDeath(SCD)causedbyventriculartachycardiasandfibrillation(VT/VF)isamajorworld-wide health problem claiming the lives of some 300,000 Americans each year. Current antiarrhythmic drug (AAD) therapy to control VT/VF is largely empirical and poorly efficacious with considerable risk of proarrhythmic effects. There remains considerable unmet need for new, safe and effective AADs that specifically target the electrophysiological underpinnings of VT/VF without compromising cardiac function. Our goal is to discover anddevelopasmallmoleculeantiarrhythmicdrugthatwilladdressthisneed. MembersoftheCardiovascularResearchLaboratoryatUCLA,Drs.HrayrKaragueuzianandRiccardoOlcese, have recently advanced our understanding of the functional regulation of the voltage dependent calcium channel CaV1.2 by the ?2?-1 subunit, and how modulation of CaV1.2 gating can reduce VT/VF triggered by early afterdepolarizations (EADs). They have also demonstrated the effect of gabapentinoids as CaV1.2 channel gating modifiers, and with this uncovered their potential therapeutic application as AADs. However, while efficacious, gabapentinoids also produce undesirable centrally mediated side effects that must be avoided in a well-tolerated chronically dosed AAD. This goal can be achieved through the design of peripherally restricted ?2?-1 ligands, i.e., compounds that are orally bioavailable but not centrally penetrant, whichweaimtodiscover. In preliminary work, Numerate has built predictive computational models for binding to ?2?-1 and for being a substrate for the drug efflux pump P-glycoprotein (P-gp). These models will allow us to efficiently identify compoundsthatarelikelytobeperipherallyrestricted,high-affinityligandsforthegabapentinoidsiteon?2?-1. Aninitialinsilicoscreenof9millioncommerciallyavailablecompoundsidentifiedaseriesofcompoundsthat are predicted to be ligands for the ?2? channel subunit, and that also have a high likelihood of being peripherallyrestricted.Wewillselectcompoundsfromthisscreenfortesting. In this SBIR grant proposal Numerate proposes to collaborate with Drs. Hrayr Karagueuzian and Riccardo Olcese at the UCLA Cardiovascular Research Laboratory in order to (1.) discover high-affinity, peripherally restricted ?2?-1 ligands, and (2.) demonstrate their ability to modulate CaV1.2 channel gating and suppress EAD-triggeredVT/VFincellbasedassaysandanisolatedintactheartmodel.